Indole alkaloids, synthesis

A series of papers have been published by Lounasmaa et al. (122-128) on the synthesis of different alkaloid-like indolo[2,3-a]quinolizidine derivatives by means of reduction and subsequent cyclization of A-[2-(indol-3-yl)ethyl]piridi-nium salts, developed as a general method for indole alkaloid synthesis by Wenkert and co-workers (129, 130). Aimed at the total synthesis of vallesiachotamine (9), valuable model studies were reported (131-133). Reduction of pyridinium salts 183 and 184 with sodium dithionite and subsequent acid-induced cyclization represents a convenient method for preparing val-lesiachotamine-type derivatives 185 and 186, respectively. 

Bosch s group cross-coupled both 2- and 3-indolylzinc derivatives with diversely substituted 2-halopyridines to assemble 2- and 3-(2-pyridyl)indoles, which have become important intermediates in indole alkaloid synthesis [23-28]. Thus, l-(phenylsulfonyl)indole (30) was converted to 2-indolylzinc reagent 32, which was then coupled with 2-halopyridine 33 to secure 2-(2-pyridyl)indole 34. 

The Pictet-Spengler route to tetrahydro-P-carbolines is frequently used in indole alkaloid synthesis, and much attention has been devoted in recent years to the development of enantiospecific Pictet-Spengler reactions and the factors which influence the diastereochemistry at C-l and C-3 (c.f 1). The diester la was prepared from 2 as 1 1 mixture of diastereomers and heated in 2% ethanolic hydrogen chloride for 3 hours in an attempt to effect epimerisation at C-l and increase the amount of trans isomer. The product, however, was 2, which was isolated in 76% yield. Heating of the cis and trans diesters 1 separately in ethanolic hydrogen chloride for 3 hours also gave 2. By comparison, when a cis, trans mixture (39 61) of lb was stirred in a mixture of methylene chloride and trifluoroacetic acid at room temperature for 90 minutes the trans diester was obtained in 96% yield. 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

GANTET, P IMBAULT, N THIERSAULT, M., DOIREAU, P Necessity of a functional octadecanoic pathway for indole alkaloid synthesis by Catharanthus roseus cell suspensions cultured in an auxin-starved medium. Plant Cell Physiol., 1998,39,220-225. 

Indole alkaloids, synthesis and biosynthesis of 87H(25)617. Yohimbine, total synthesis of 90YGK206. 

Since the monumental accomplishments of Woodward s total syntheses of strychnine in 1954 [I] and rcserpinc in 1958 (2], the arsenal of synthetic methods in indole alkaloid synthesis has greatly expanded. In the same time period, the use of palladium chemistry in organic syntheses has also witnessed tremcndou- growth with an ever-expanding repc loire of synthetic methods and their applications to total synthesis. The use of palladium chemistry for the synthesis of indole alkaloids has been explored, and several examples have been included in recent reviews [3-6]. This account attempts to present a comprehensive collection of total syntheses of naturally occurring indole alkaloids where palladium chemistry plays a central role in the syntheses. 

Scheme 10. Application of Suzuki coupling in natural indole alkaloid synthesis...

An indole alkaloid synthesis employing a bona fide intramolecular Heck reaction was documented in Sundberg s preparation of 5,6-homoiboga derivatives [90]. Several attempts to construct S,6-homoiboga derivative 191 using inter- or intramolecular Heck reaction conditions with phosphine ligands led to poor yields. Application of Jeffery s ligand-free" phase-transfer... 

A neat, biogenetically-patterned conversion of stemmadenine (175) and its O-acetate (176) into vallesamine (177) and its O-acetate (178) provides yet another application of the Polonovski reaction in indole alkaloid synthesis (Scheme 24). The facility of this transformation suggests that the Nb-oxides may be the actual biogenetic precursors of the alkaloids lacking C-5, and that decarboxylative loss of C-22, implicit in the biogenetic pathway proposed earlier for apparicine, is not necessary. 

Now I am going to talk on the second part of our indole alkaloid synthesis. 

---